Manganese (Mn) is an environmental neurotoxicant. A direct neurotoxic effect has been observed primarily in individuals exposed to Mn occupationally. Mn also has been implicated as a possible etiologic agent in Parkinson's disease. The ultimate goal of the proposed research is to understand the cellular and molecular basis of manganese neurotoxicity. The global and working hypothesis is that glial cells modulate Mn neurotoxicity. This research proposal will focus on the interactions between glial cells, particularly astrocytes and microglia, and neurons in manganese toxicity. The proposed research will use primary cell culture model systems (fetal rat striatal and mesencephalic neurons, and neonatal rat astrocytes and microglia, alone and in co-culture). We will test the hypotheses that 1) neuronal death in response to Mn2+ exposure is mediated by mitochondrial dysfunction; 2) astrocytes and/or microglia modulate their uptake or release of soluble factors in response to Mn2+ exposure, and 3) that modulation of neurotoxicity in response to Mn2+ exposure is related to glial uptake and compartmentalization of Mn2+. Investigating the cellular and molecular mechanisms of Mn neurotoxicity will yield fundamental information necessary for the development of therapeutic intervention in affected individuals, and may contribute to our understanding of the mechanisms of other neurodegenerative disorders such as Huntington's Disease and Parkinson's Disease.